1,2,4-Triazines for treating gastrointestinal motility dysfunction

ABSTRACT

Method for treating gastrointestinal motility dysfunctions using 1,2,4-triazines.

FIELD OF THE INVENTION

This invention relates to a method for treating gastrointestinaldisorders and in particular gastrointestinal motility dysfunctions suchas the disorder known as irritable bowel syndrome (IBS).

Irritable bowel syndrome is one of the most common physical disordersobserved in the practice of gastroenterology. It is typically a chroniccondition characterized by abdominal pain and an alteration in bowelhabits which are not due to any identifiable anatomical abnormality.Gross symptoms include either diarrhea or constipation or periodswherein patients experience both conditions. Furthermore, IBS patientsfrequently suffer from a heightened level of anxiety.

In recent years, investigators have characterized IBS as a primarydisorder of intestinal motility, that is, a disturbance in the normalmovement of intestinal contents. It has been found that patients withIBS exhibit abnormal electrical patterns in the intestinal smooth muscleboth in the unstimulated basal state as well as subsequent to intestinalstimulation. By way of background, the electrical activity of intestinalsmooth muscle in normal patients demonstrates both a pattern of slowwaves and spike potentials. The slow waves are phasic undulations in theelectric potential of the smooth muscle membrane and are presentthroughout the intestinal tract. The spike potential activity reflectsthe electrical stimulus initiating smooth muscle contraction andincreases following meals and stimulation.

IBS patients exhibit abnormal slow wave patterns and abnormal spikepotential patterns both in the basal state and in response to meals.Additionally, IBS patients experience increases in segmental electricalactivity in response to stimuli such as cholecystokinin, neostigmine,stress, and distension of portions of the intestinal tract. Segmentalelectrical activity is manifested by the contraction of isolated unitsof circular smooth muscle that constrict the bowel lumen. Thisconstriction is non-propulsive and is believed to result in impedence tothe flow of the intestinal contents. It has been suggested thatincreased segmental activity may result in constipation, and thatdecreased segmental activity may be associated with diarrhea.

A basic abnormality in the electrical pattern of IBS patients is themarked increase in the incidence of slow wave activity occuring at afrequency of 3 cycles per minute, in contrast to the predominant slowwave frequency in normal patients of 6 cycles per minute. Anotherstriking difference between normal patients and IBS patients isreflected in the contractile activity exhibited subsequent to theingestion of a meal. In a normal patient, colonic contractile activitywill increase rapidly to 3 to 4 times its basal level for a period ofabout half an hour, and return to the fasting level 50 minutes later. Incontrast, the contractile activity in IBS patients reaches a peak at70-90 minutes but never reaches the maximum activity of the normalpatient. As a result of this abnormal condition, the IBS patientexperiences ineffective movement of the gastrointestinal contents, unduedistension of the intestinal tract and heightened pain sensitivity toabdominal pressure.

The present invention relates to a method of restoring the intestinalfunction of an IBS patient to normal levels.

REPORTED DEVELOPMENTS

In human clinical studies, anticholinergic drugs such as clidiniumbromide have been found to moderate the abnormal colonic contractionactivity in IBS patients following a meal, but such therapy does notnormalize the intestinal function of an IBS patient. Indeed, it has beenreported that the response to anticholinergic drugs is markedlydifferent in normal and IBS patients, and it has been suggested that thepersistence of the abnormal slow wave frequency regardless of symptomsor therapy reflects the predisposition of IBS patients to respond tovarious stimuli in an abnormal fashion. For a recent discussion of IBS,see H. Tucker and M. M. Schuster, Irritable Bowel Syndrome: NewerPathophysiologic Concepts, "Advances in Internal Medicine," Vol. 27, pp183-204, hereby incorporated by reference.

Other drugs suggested for use in IBS treatment include diphenoxylate.When diarrhea is present, diphenoxylate in combination with stoolsofteners has been suggested as a treatment. However, diphenoxylatepossesses morphine-like properties and therefore, its use may result inintestinal spasms, respiratory depression and narcotic dependence.

Mild sedation with phenobarbitol or tranquilizers such as Librax® hasalso been suggested for the treatment of IBS.

In U.S. Pat. No. 4,239,768, N-aryl-N'-(2-imidazolidinylidine) ureacompounds are disclosed as being useful in the treatment of IBS. Thereis no disclosure in the '768 that the imidazolidinylidene compounds havebeen found useful in human clinical studies.

SUMMARY OF THE INVENTION

This invention relates to a method for treating a patient suffering froma gastrointestinal motility dysfunction by medicating said patient witha therapeutic amount of a 3,5-diamino-6-(substitutedphenyl)-1,2,4-triazine. The 1,2,4-triazines useful in the presentinvention may be represented by Formula I ##STR1## wherein: R and R₁ maybe the same or different and are hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylloweralkyl, alkoxyloweralkyl,aralkoxyloweralkyl or aralkyl;

R₂, R₃, R₄, R₅ and R₆ may be the same or different and are hydrogen,halo, loweralkyl, haloloweralkyl, nitro, amino, acylamino, hydroxy,aralkyloxy or loweralkoxy;

R and R₁ together may form a 5-7 atom ring which may further include 0-1hetero atoms of N, O or S; and

provided at least one of R₂ and R₆ is other than hydrogen;

and the pharmaceutically acceptable salts thereof.

Many of these compounds are known and, for example, are disclosed inU.S. Pat. No. 4,311,701 as having antibacterial, antimalarial andanticonvulsant activity. None of these patents discloses that thecompounds described therein are useful for treating IBS or othergastrointestinal motility dysfunctions.

DETAILED DESCRIPTION

Compounds for use in this invention which are preferred include thosewhere:

R₂, R₃, R₄, R₅ and R₆ are hydrogen, halo, loweralkyl, haloloweralkyl,nitro or loweralkoxy;

R and R₁ are hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyloweralkyland aralkoxyalkyl; or

R and R₁ together may be alkylene;

provided that at least one of R₂ or R₆ is other than hydrogen.

The more preferred compounds for use in the present invention includethose where:

R and R₁ are hydrogen or loweralkyl; or R and R₁ together may bealkylene;

R₂ is hydrogen or loweralkyl;

R₃ and R₅ are hydrogen;

R₄ is hydrogen, loweralkyl or halo;

R₆ is loweralkyl, nitro, alkoxy or halo.

The most preferred compounds for use in the method of the presentinvention are those where:

R is hydrogen;

R₁ is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,sec-butyl, t-butyl, pentyl, hexyl, heptyl, allyl, propargyl,methoxyethyl, ethoxyethyl, benzyloxyethyl; or

R and R₁ together may be tetramethylene, pentamethylene andhexamethylene;

R₂ is hydrogen, methyl or ethyl;

R₃ and R₅ are hydrogen;

R₄ is hydrogen, methyl, ethyl, chloro or bromo;

R₆ is hydrogen, methyl, ethyl, nitro, methoxy, ethoxy, chloro, bromo orfluoro.

A special embodiment of this invention comprises the treatment of IBSpatients by the administration of the above compounds which have:

R₂ -loweralkyl substitution;

R₂, R₆ -diloweralkyl substitution;

R₂, R₆ -loweralkyl, alkoxy substitution;

R₂, R₆ -loweralkyl, halo substitution;

R₂, R₆ -alkyl, nitro substitution;

R₂, R₄, R₆ -triloweralkyl substitution, or

R₂, R₄, R₆ -loweralkyl, dihalo substitution.

A further special embodiment of this invention comprises the use ofcompounds which have: R₂, R₆ -dihalo substitution.

A further special embodiment of this invention comprises the use ofcompounds which have:

R and R₁ are hydrogen;

R₂, R₃ and R₄ are each independently hydrogen or chloro; and

R₅ and R₆ are hydrogen; provided at least one of R₂, R₃ and R₄ is otherthan hydrogen.

It is well known in the pharmacological arts that non-toxic acidaddition salts of pharmacologically active amine compounds do not differin activities from their free base. The salts provide a water solubleform of the compounds.

The amines of this invention may be readily converted to their non-toxicacid addition salts by customary methods in the art. The non-toxic saltsof this invention are those salts the acid component of which ispharmacologically acceptable in the intended dosages. Such salts includethose prepared from inorganic acids, organic acids, higher fatty acids,high molecular weight acids. Examples of such salts are:

    ______________________________________                                        hydrochloric acid,    succinic acid,                                          hydrobromic acid,     glycolic acid,                                          sulfuric acid,        lactic acid,                                            nitric acid,          salicylic acid,                                         phosphoric acid,      benzoic acid,                                           methane sulfonic acid,                                                                              nicotinic acid,                                         benzene sulfonic acid,                                                                              phthalic acid,                                          acetic acid,          stearic acid,                                           propionic acid,       oleic acid,                                             malic acid,           abietic acid.                                           ______________________________________                                    

"Alkyl" means an aliphatic saturated hydrocarbon of one to about tencarbon atoms.

"Loweralkyl" means an alkyl hydrocarbon group from one to about fivecarbon atoms.

"Alkenyl" means an unsaturated hydrocarbon chain having about two toabout seven carbon atoms and having one to about three double bonds.

"Alkynyl" means an unsaturated hydrocarbon chain having about two toabout seven carbon atoms and having one to about three triple bonds.

"Cycloalkyl" means a saturated cyclic hydrocarbon group having three toabout seven carbon atoms.

"Cycloalkenyl" means an unsaturated cyclic hydrocarbon group havingabout five to about seven carbon atoms and having one to about threedouble bonds.

"Loweralkoxy" means an alkoxy group containing from one to about fivecarbon atoms.

The preferred "aryl" group is phenyl.

The preferred "aralkyl" groups are benzyl and phenethyl.

The preferred "haloloweralkyl" group is trifluoromethyl.

The preferred "haloloweralkoxy" group is trifluoromethoxy.

The compounds of this invention may be prepared according to the methodsknown in the art and methods described in U.S. Pat. No. 3,637,688 andU.K. Pat. No. 759,014, hereby incorporated by reference.

During the course of human clinical studies, it has been found that thecondition of many IBS patients improves significantly when thesepatients are administered a pharmaceutical composition including acompound which exhibits positive activity in the pharmacological testprocedures described below.

Charcoal Motility

This procedure measures the effect of test compounds on normalintestinal motility.

A charcoal suspension (10 ml/kg of a 10% suspension of activatedcharcoal, U.S.P. in 0.5% methylcellulose) is given orally to groups oflaboratory mice 30 minutes after an oral dose of the test compound orvehicle. The mice are sacrificed 30 min after receiving the charcoal andthe intestines are carefully removed without stretching and placedlengthwise on moist paper. The length of intestine (pyloric sphincter tocaecum) and the distance traveled by the charcoal as a fraction of thatlength are evaluated for each animal and group means are compared andexpressed as percentage inhibition.

Castor Oil Induced Diarrhea

Castor oil diarrhea is the result of both altered motility and increasedintestinal secretions. This procedure measures the effectiveness of testcompounds on abnormal motility and hypersecretory intestinal states.Male Swiss-Webster mice (25-30 g) or female Wistar rats (180-210 g) aredosed orally with a test compound or vehicle 1 h before receiving astandard dose of castor oil orally (0.3 ml in mice, 1.0 ml in rats). Theanimals are individually caged and examined for the presence of diarrheahourly for 6 h after castor oil challenge. Diarrhea is defined as thepresence in the stools of fluid material which stained the absorbentpaper placed beneath the cage. Control animals had 100% incidence ofdiarrhea at 3 h in mice and 4 h in rats. For tolerance studies both maleand female Wistar rats (140-160 g) are given the test compound at dosesof 2, 10 and 50 mg/kg once daily for 14 consecutive days. Five rats(fasted overnight) per dose per sex and appropriate controls arechallenged with castor oil on days 1, 2, 7 and 14 of the experiment. Onthe test days, test compound or vehicle is given as usual and 1 h laterthe animals are challenged with castor oil and observed for diarrhea asdescribed above.

Isolate Guniea Pig Ileum Test

Sections of the terminal ileum of guinea pigs, 2-3 cm long, aresuspended in a 50-ml bath of Tyrode solution (37° C., pH 7.5) at 0.5 gtension and oxygenated with 95% O₂ -5% CO₂. Isometric contractions arerecorded with a Grass force displacement transducer and a Beckmandynograph with a strain-gauge coupler. Isotonic contractions arerecorded with a Harvard isotonic smooth muscle transducer and a Beckmandynograph. A concentrated spasmogen solution of histamine,cholecystokinin, BaCl₂, serotonin, dimethyl phenyl piperiziniumchloride, PEG₂ or acetylcholine is added to the bath. Both cumulativeand single doses of spasmogens are used. The concentration of testcompound necessary to halve the spasmogenic response (ID₅₀) isdetermined at levels of the test compound that gave approximately 75% ofthe maximum response (ED₇₅).

It is believed that the IBS effective compound described above alsoexhibits a positive response in connection with the following testprocedures.

Charcoal Motility--Abnormal Motility Induced by Neostigmine andQuinidine

The test procedure is described in the following references, herebyincorporated by reference:

Schuster, Gastrointestinal Disease, p. 880 (1983); and Garrett et al,Gut, 7:562 (1966).

Isolated Rabbit Duodenum Test

This assay measures the direct spasmolytic effect of test compound onintestinal circular smooth muscle. Segments of rabbit duodenum, 2-3 cmlong, are suspended in a 50-ml bath of Ringer's solution (37° C., pH7.3) at 0.5 g tension and oxygenated with 95% O₂ -5% CO₂. A concentratedspasmogen solution of morphine, cholecystokinin, PEG₂ or acetylcholineis added to the bath in cumulative and single doses. The maximumresponse to each drug is taken as 100% and all lesser responses arecalculated as a percentage of the maximum response. Contractions arerecorded with a Grass force displacement transducer and a Beckmandynograph with a strain-gage coupler. The concentration of test compoundnecessary to halve the spasmogenic response (ID₅₀) is determined atlevels of the test compound that give approximately 75% of the maximumresponse (ED₇₅).

Intestinal Motility in Anesthetized Dogs

This procedure measures the effect of the test compounds on intestinalcircular and longitudinal smooth muscle contractions both in the basalstate and stimulated state. Treatment of the subject animal withspasmogens such as cholecystokinin and PEG2 produces modified motilitypatterns useful for studying the motility normalizing effect of the testcompounds. Female beagle dogs are implanted under aseptic conditionswith 8 extraluminal contractile force strain-gauge transducers. Prior torecording intestinal contractile activity, the dogs are anesthetizedwith sodium pentobarbitol (35 mg/kg i.v.). Contractile activity ismonitored from the circular axis of the proximal and mid-duodenum, twosites on the terminal ileum and the proximal and mid-colon. The ilealsites are also monitored for longitudinal contractile activity.Contractions are recorded on a Beckman Dynograph. The response ofintestinal motility in both fed and fasted states to several doses ofthe test compound is recorded. For recording of fasted intestinalactivity, the dogs are not fed (water ad libitum) for 18 h prior to thestart of recording; fed animals are given 450 g of canned dog foodimmediately before the experiment.

It is also believed that a further indication of IBS effectiveness islocal anesthetic activity.

The compounds described above have a useful degree of effectiveness intreating a patient suffering from irritable bowel syndrome and othergastrointestinal motility dysfunctions. These compounds may beadministered to the patient either orally or parenterally. The preferredroute of administration is by oral means in the form of tablets, aqueousor oily suspensions, dispersible powders or granules, emulsions, hard orsoft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apharmaceutically elegant and palatable preparation. Tablets whichcontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients are suitable for the manufactureof tablets. These excipients may be the following: inert diluents, forexample, calcium carbonate, sodium carbonate, lactose, calcium phosphateor sodium phosphate; granulating and disintegrating agents, for example,maize starch or alginic acid; binding agents, for example, starch,gelatin or acacia; and lubricating agents, for example, magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with an oilmedium, for example, arachis oil, liquid paraffin or olive oil.

Aqueous solutions may be formulated using the following excipients:suspending agents, for example, sodium carboxymethyl-cellulose,methyl-cellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidine, gum tragacanth and gum acacia; dispersing orwetting agents such as a naturally occurring phosphatide, for example,lecithin; condensation products of an alkylene oxide with fatty acids,for example, polyoxyethylene stearate; condensation products of ethyleneoxide with long-chain aliphatic alcohols, for example,heptadecaethyleneoxy-cetanol; condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol, for example,polyoxyethylene sorbitol mono-oleate; or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example, polyoxyethylene sorbitan mono-oleate. The saidaqueous suspensions may also contain one or more flavoring agents, andone or more sweetening agents, such as sucrose.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil, such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example, sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions useful in the present invention may alsobe in the form of oil-in-water emulsions. The oily phase may be avegetable oil, for example, olive oil or arachis oils, or a mineral oil,for example, liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally occurring gums, for example, gum acacia or gumtragacanth, naturally-occurring phosphatides, for example, soya beanlecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan mono-oleate. The emulsions mayalso contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, sorbitol or sucrose. Such formulations may alsocontain a demulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterileinjectionable preparation, for example, as a sterile injectable aqueoussuspension. This suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, for example, as an aqueoussolution buffered to a pH of 4.0 to 7.0 and made isotonic with sodiumchloride.

Further, the active compound may be administered alone or in admixturewith other agents having the same or different pharmacologicalproperties.

Further, these compounds may be tableted or otherwise formulated fororal use so that for every 100 parts by weight of the composition, thereare present between about 5 and about 95 parts by weight of the activeingredient. The dosage unit form will generally contain between about0.1 mg and about 50 mg of the active ingredients of this invention. Thepreferred unit dose is between about 0.5 mg and about 10 mg. Thecompositions may be taken 1-8 times daily depending on the dosage unitrequired.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective in thetreatment of irritable bowel syndrome. In general, the oral daily dosecan be between about 0.01 mg/kg and about 1 mg/kg (preferably in therange of 0.05-0.50 mg/kg/day), bearing in mind, of course, that inselecting the appropriate dosage in any specific case, considerationmust be given to the patient's weight, general health, age, and otherfactors which may influence response to the drug.

Parenteral administration may be carried out using comparative dosagestaken from the oral compositions. In general, the parenteral dosage willbe less than the oral dose and normally within the range of 1/2 to 1/10the oral dose but, of course, this would depend on the absorptioncharacteristics of the compound employed. Dosages would be in thecustomary manner; however, in general, parenteral administration may becarried out neat or the compound may be utilized with a sterile vehicleas mentioned above. Dosage unit forms between 0.1 mg and 50 mg andpreferably in the range of 1 mg and 10 mg are useful. The dailyparenteral dose would be between 0.002 mg/Kg/day and 0.2 mg/Kg/day andpreferably in the range of 0.01 mg/Kg and 0.1 mg/Kg/day.

The way in which IBS affects individuals can vary from one individual toanother. For example, there are patients who have the condition foryears, indeed most, if not all, of their lives. As noted above, IBS isbelieved to be a dysfunction in intestinal motility resulting in a rangeof distressing symptoms which increase or decrease in severity as aresult of any number of factors, including stress. Some IBS patients mayappear relatively free of the syndrome for days, weeks or even months,but experience acute episodes at any given time. On the other hand,other patients may suffer a higher and relatively constant incidence ofsymptoms such as abdominal pain and alternating periods of diarrhea andconstipation.

The present invention provides an IBS patient with a choice of therapy.Since some normalizing effect is usually experienced relatively quickly,for example, within an hour to within about a day or two after the startof medication pursuant. to the invention, the patient may be medicatedfor short periods of time, for example, on a daily basis for about a dayto about two weeks to avoid acute occurences of IBS symptoms at times ofstress or at times when other aggravating factors are present. Suchacute therapy may be discontinued when aggravating factors abate, andresumed when the patient feels that continued therapy would bebeneficial. For those patients experiencing a remission of theunderlying motility dysfunction, therapy may be discontinued. On theother hand, patients who are constantly being troubled by the discomfortof IBS symptoms may require continuous or maintenance therapy whichinvolves medication on an essentially continuing daily basis.Observations of various patients have revealed that, soon after thediscontinuance of therapy, IBS symptoms reappear. For such patients,medication on a maintenance basis appears to be in order.

We claim:
 1. A method for treating a irritable bowel syndrome comprisingmedicating a patient suffering from a irritable bowel syndrome with atherapeutically effective amount of a 3,5-diamino-6-(substitutedphenyl)-1,2,4-triazine.
 2. A method according to claim 1 where saidtriazine is of the formula ##STR2## wherein: R and R₁ may be the same ordifferent and are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylloweralkyl, alkoxyloweralkyl, aralkoxyloweralkylor aralkyl;R₂, R₃, R₄, R₅ and R₆ may be the same or different and arehydrogen, halo, loweralkyl, haloloweralkyl, nitro, amino, acylamino,hydroxy, aralkoxy or loweralkoxy; R and R₁ together may form a 5-7 atomring which may further include 0-1 hetero atoms of N, O or S; andprovided at least one of R₂ and R₆ is other than hydrogen; and thepharmaceutically acceptable salts thereof.
 3. A method according toclaim 2 wherein:R and R₁ are hydrogen, loweralkyl, alkenyl, alkynyl,alkoxyloweralkyl and aralkoxyalkyl; or R and R₁ together may bealkylene; R₂, R₃, R₄, R₅ and R₆ are hydrogen, halo, loweralkyl,haloloweralkyl, nitro or loweralkoxy; provided that at least one of R₂or R₆ is other than hydrogen.
 4. A method according to claim 3 wherein:Rand R₁ are hydrogen or loweralkyl; or R and R₁ together may be alkylene;R₂ is hydrogen or loweralkyl; R₃ and R₅ are hydrogen; R₄ is hydrogen,loweralkyl or halo; and R₆ is loweralkyl, nitro, alkoxy or halo.
 5. Amethod according to claim 2 wherein:R is hydrogen; R₁ is hydrogen,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, t-butyl,pentyl, hexyl, heptyl, allyl, propargyl, methoxyethyl, ethoxyethyl orbenzyloxyethyl; or R and R₁ together may be tetramethylene,pentamethylene and hexamethylene; R₂ is hydrogen, methyl or ethyl; R₃and R₅ are hydrogen; R₄ is hydrogen, methyl, ethyl, chloro or bromo; R₆is methyl, ethyl, nitro, methoxy, ethoxy, chloro, bromo or fluoro.
 6. Amethod according to claim 3 wherein:R₂ is loweralkyl; R₆ is hydrogen,loweralkyl, alkoxy, halo or nitro; and R₃, R₄ and R₅ are hydrogen.
 7. Amethod according to claim 3 wherein:R₂ is loweralkyl; R₄ and R₆ are eachindependently halo or loweralkyl; R₃ and R₅ are hydrogen.
 8. A methodaccording to claim 3 wherein:R₂ and R₆ are halo; and R₃, R₄ and R₅ arehydrogen.
 9. A method according to claim 2, wherein:R, R₁, R₅ and R₆ arehydrogen; and R₂, R₃ and R₄ are each independently hydrogen or chloro;provided at least one of R₂, R₃ and R₄ is other than hydrogen.
 10. Amethod according to claim 2 wherein the compound is3,5-diamino-6-(2,4-dichlorophenyl)-1,2,4 triazine.
 11. A methodaccording to claim 2 wherein the compound is3,5-diamino-6-(2-chlorophenyl)-1,2,4-triazine.
 12. A method for thetreatment of irritable bowel syndrome comprising medicating the patientsuffering from irritable bowel syndrome 1 to 8 times a day with atherapeutically effective amount of about 0.5 to about 10 mg of acompound according to the formula ##STR3## wherein: R and R₁ may be thesame or different and are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylloweralkyl, alkoxyloweralkyl, aralkoxyloweralkylor aralkyl;R₂, R₃, R₄, R₅ and R₆ may be the same or different and arehydrogen, halo, loweralkyl, haloloweralkyl, mitro, amino, acylamino,hydroxy, aralkoxy or loweralkoxy; R and R₁ together may form a 5-7 atomring which may further include 0-1 hetero atoms of N, O or S; andprovided at least one of R₂ and R₆ is other than hydrogen; and thepharmaceutically acceptable salts thereof.